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- PDB-6wv1: Crystal Structure of Recombinant Human Acetylcholinesterase In Co... -

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Basic information

Entry
Database: PDB / ID: 6wv1
TitleCrystal Structure of Recombinant Human Acetylcholinesterase In Complex with GB and HI-6
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / nerve agent / acetylcholinesterase / tabun / GA
Function / homology
Function and homology information


negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholine receptor signaling pathway ...negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholine receptor signaling pathway / osteoblast development / acetylcholinesterase activity / Synthesis of PC / basement membrane / regulation of receptor recycling / Synthesis, secretion, and deacylation of Ghrelin / synaptic cleft / synapse assembly / side of membrane / laminin binding / collagen binding / positive regulation of protein secretion / neuromuscular junction / receptor internalization / positive regulation of cold-induced thermogenesis / amyloid-beta binding / nervous system development / retina development in camera-type eye / hydrolase activity / cell adhesion / synapse / perinuclear region of cytoplasm / Golgi apparatus / cell surface / protein homodimerization activity / extracellular space / extracellular region / nucleus / membrane / plasma membrane
Similarity search - Function
Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / : / Cholinesterase / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-7PE / Chem-HI6 / propan-2-yl hydrogen (S)-methylphosphonate / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.372 Å
AuthorsMcGuire, J.R. / Bester, S.M. / Pegan, S.D. / Height, J.J.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Threat Reduction Agency (DTRA)CB#3889 United States
CitationJournal: Chem.Res.Toxicol. / Year: 2021
Title: Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6.
Authors: McGuire, J.R. / Bester, S.M. / Guelta, M.A. / Cheung, J. / Langley, C. / Winemiller, M.D. / Bae, S.Y. / Funk, V. / Myslinski, J.M. / Pegan, S.D. / Height, J.J.
History
DepositionMay 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acetylcholinesterase
B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,64111
Polymers118,8942
Non-polymers2,7479
Water7,440413
1
A: Acetylcholinesterase
hetero molecules

B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,64111
Polymers118,8942
Non-polymers2,7479
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545y,x-1,-z1
Buried area5840 Å2
ΔGint26 kcal/mol
Surface area38230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.183, 104.183, 323.760
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Acetylcholinesterase / AChE


Mass: 59447.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACHE / Production host: Homo sapiens (human) / References: UniProt: P22303, acetylcholinesterase

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Sugars , 2 types, 4 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 418 molecules

#4: Chemical ChemComp-7PE / 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL / POLYETHYLENE GLYCOL FRAGMENT


Mass: 310.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O7
#5: Chemical ChemComp-UCJ / propan-2-yl hydrogen (S)-methylphosphonate


Mass: 138.102 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H11O3P / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-HI6 / 4-(AMINOCARBONYL)-1-[({2-[(E)-(HYDROXYIMINO)METHYL]PYRIDINIUM-1-YL}METHOXY)METHYL]PYRIDINIUM / 1-(2-HYDROXY-IMINOMETHYLPYRIDINIUM)-1-(4-CARBOXYAMINO)-PYRIDINIUM DIMETHYLETHER


Mass: 288.302 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16N4O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 413 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.27 Å3/Da / Density % sol: 71.17 % / Mosaicity: 0.369 °
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: PEG 3350, KNO3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.37→50 Å / Num. obs: 83198 / % possible obs: 99.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 41.71 Å2 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.042 / Rrim(I) all: 0.082 / Χ2: 1.491 / Net I/σ(I): 17.6 / Num. measured all: 276379
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.37-2.413.20.34341010.9270.2180.4081.107100
2.41-2.453.40.30140950.9420.190.3581.136100
2.45-2.53.40.2741530.9520.1690.321.185100
2.5-2.553.40.23140830.9620.1460.2741.167100
2.55-2.613.40.2141440.9640.1320.2491.211100
2.61-2.673.30.19341270.970.1220.231.43499.7
2.67-2.743.40.1641340.980.10.1891.38899.9
2.74-2.813.40.13441440.9850.0830.1581.404100
2.81-2.893.40.11641290.9890.0710.1371.436100
2.89-2.993.40.10141330.9870.0620.121.549100
2.99-3.093.40.09141100.9860.0550.1071.63199.9
3.09-3.223.30.08941850.9910.0540.1051.74699.9
3.22-3.363.40.08441570.9910.050.0981.77399.9
3.36-3.543.30.07841600.9920.0460.0911.82199.7
3.54-3.763.30.06641640.9910.040.0781.72399.6
3.76-4.053.30.05841590.9940.0350.0681.66999.5
4.05-4.463.30.05442040.9940.0330.0641.899.4
4.46-5.13.30.05742320.9930.0350.0671.63499.5
5.1-6.433.30.04942600.9940.030.0581.60398.6
6.43-503.20.03743240.9970.0240.0451.38295.5

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.17.1-3660refinement
PDB_EXTRACT3.25data extraction
PHENIX1.17.1-3660phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EY4

4ey4


Resolution: 2.372→37.015 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1988 4141 4.99 %
Rwork0.1663 78905 -
obs0.1679 83046 99.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 139.72 Å2 / Biso mean: 51.0334 Å2 / Biso min: 22.93 Å2
Refinement stepCycle: final / Resolution: 2.372→37.015 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8265 0 202 413 8880
Biso mean--94.53 55.42 -
Num. residues----1063
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0058851
X-RAY DIFFRACTIONf_angle_d0.76612115
X-RAY DIFFRACTIONf_chiral_restr0.0481298
X-RAY DIFFRACTIONf_plane_restr0.0061592
X-RAY DIFFRACTIONf_dihedral_angle_d4.2527003
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3721-2.3990.28431320.2272247396
2.399-2.42720.26851200.2182634100
2.4272-2.45680.24151580.21562586100
2.4568-2.48790.27681010.20832689100
2.4879-2.52070.2671260.19962560100
2.5207-2.55520.25371430.20292633100
2.5552-2.59170.2441560.19282567100
2.5917-2.63040.26251260.192608100
2.6304-2.67140.23221580.19172643100
2.6714-2.71520.22281170.19132545100
2.7152-2.7620.22551540.18262668100
2.762-2.81220.24921630.17992582100
2.8122-2.86630.21751180.18242626100
2.8663-2.92480.19511050.17482640100
2.9248-2.98840.20781390.16722667100
2.9884-3.05780.20421360.16532633100
3.0578-3.13430.18941370.17012590100
3.1343-3.2190.22671450.18052624100
3.219-3.31360.20931570.17342587100
3.3136-3.42050.1961500.16752638100
3.4205-3.54270.2121370.1642265699
3.5427-3.68440.1891210.15742633100
3.6844-3.85190.16071240.1482268199
3.8519-4.05480.1771320.1413264399
4.0548-4.30850.18221540.1404265099
4.3085-4.64050.15521350.1296265799
4.6405-5.10650.13831300.13972688100
5.1065-5.84290.20671700.1652267299
5.8429-7.35190.21061440.1815269598
7.3519-37.0150.18991530.1794273795
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.16152.40020.84263.1338-0.47943.37190.07720.0960.0276-0.3577-0.3486-0.09880.09420.78330.22430.24630.0598-0.01690.58120.05740.4313126.234523.206628.3107
21.5157-1.4193-0.67812.5785-0.16492.34920.20750.2983-0.0527-0.023-0.2697-0.16-0.04610.1120.04810.3162-0.0264-0.04150.5189-0.00080.3032106.409236.686721.9355
31.26380.240.69591.5917-0.21573.58410.04-0.07040.04890.0127-0.166-0.382-0.63280.63540.09840.4082-0.1282-0.01660.48760.12670.3554116.692452.524311.7972
41.764-0.338-1.33780.9984-0.26993.54670.13750.08420.34360.1616-0.1034-0.0341-0.71250.4125-0.03390.3944-0.0702-0.01290.32850.0620.3266103.831250.482830.7716
52.5178-0.55830.36982.3904-0.01345.42240.01070.09490.27020.0989-0.04730.1854-0.6115-0.59770.00880.26550.04320.01210.31970.00320.289291.760951.543733.0154
61.50320.577-0.36940.2233-0.20933.9942-0.11830.26420.2739-0.08060.03470.0718-0.3498-0.11850.05570.37760.0256-0.0270.36340.07970.3188100.289648.934214.3672
75.10310.9763-0.46122.3928-0.02084.05230.1147-0.23710.01690.27670.0339-0.3328-0.690.2944-0.1440.3984-0.0145-0.09950.37920.00510.274365.93737.213145.6943
82.07270.33570.92941.8495-0.05053.3415-0.0839-0.0915-0.02880.05030.0875-0.036-0.2665-0.0066-0.02510.2140.0121-0.03320.3606-0.00270.241756.577433.240834.2901
92.05140.15260.78432.4531-0.69963.24210.0348-0.0354-0.3121-0.09340.01180.08630.4664-0.93430.01230.2636-0.0594-0.02650.6110.06790.399639.159417.397733.3145
101.82391.35020.0021.03680.02892.2064-0.12680.03750.1673-0.01660.16110.1652-0.2087-0.2982-0.06830.34740.0221-0.1260.5250.08420.37348.004634.559519.3717
113.11740.4381.80562.08310.25643.22840.2989-0.3135-0.66150.37360.211-0.54450.63420.4629-0.38290.55840.1205-0.09250.4757-0.05690.448152.777310.33148.7263
121.2435-0.1942-0.01341.89141.1343.58910.15-0.0124-0.13440.001-0.1106-0.12480.24140.2924-0.12750.37390.0581-0.07220.4529-0.01560.30948.101718.05012.9588
131.86360.23740.00431.86090.35521.6-0.06940.1055-0.2385-0.19480.2149-0.2267-0.06880.4329-0.10350.3465-0.0817-0.02930.5943-0.02030.329962.971330.726716.3689
142.0567-0.8881.63611.4741-0.39982.4463-0.19620.57630.4268-0.0922-0.0074-0.3123-0.59220.64810.0960.4892-0.265-0.04350.59530.06860.421766.692141.982614.1274
152.57870.80931.48752.30070.72352.16070.2091-0.3152-0.0872-0.1839-0.2307-0.0497-0.36050.3510.01520.3702-0.0696-0.03710.51480.01190.230250.982632.34785.0155
161.8306-1.453-0.68763.37340.73361.974-0.083-0.2968-0.10420.6712-0.0297-0.04550.20540.06010.10680.3582-0.1338-0.02240.37630.05550.3109104.92131.340653.8321
171.0995-0.2532-0.21241.6399-0.09152.00620.0236-0.12630.03210.2968-0.0837-0.2378-0.17320.48490.04850.2779-0.1337-0.03540.39960.0390.3057110.992234.109544.0319
181.8366-1.7285-0.88661.78871.172.36610.0395-0.02730.00320.2297-0.0335-0.05660.09680.1554-0.01860.227-0.1027-0.00450.33650.02690.3274108.82733.4437.1745
190.5367-0.62690.23981.1184-0.00832.21270.09440.1571-0.11250.0048-0.11710.15690.1075-0.10550.02340.2067-0.0915-0.01570.3224-0.00140.3441103.603530.12731.1112
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 255 through 288 )B255 - 288
2X-RAY DIFFRACTION2chain 'B' and (resid 289 through 341 )B289 - 341
3X-RAY DIFFRACTION3chain 'B' and (resid 342 through 406 )B342 - 406
4X-RAY DIFFRACTION4chain 'B' and (resid 407 through 466 )B407 - 466
5X-RAY DIFFRACTION5chain 'B' and (resid 467 through 513 )B467 - 513
6X-RAY DIFFRACTION6chain 'B' and (resid 514 through 542 )B514 - 542
7X-RAY DIFFRACTION7chain 'A' and (resid 3 through 45 )A3 - 45
8X-RAY DIFFRACTION8chain 'A' and (resid 46 through 237 )A46 - 237
9X-RAY DIFFRACTION9chain 'A' and (resid 238 through 300 )A238 - 300
10X-RAY DIFFRACTION10chain 'A' and (resid 301 through 341 )A301 - 341
11X-RAY DIFFRACTION11chain 'A' and (resid 342 through 366 )A342 - 366
12X-RAY DIFFRACTION12chain 'A' and (resid 367 through 406 )A367 - 406
13X-RAY DIFFRACTION13chain 'A' and (resid 407 through 466 )A407 - 466
14X-RAY DIFFRACTION14chain 'A' and (resid 467 through 513 )A467 - 513
15X-RAY DIFFRACTION15chain 'A' and (resid 514 through 542 )A514 - 542
16X-RAY DIFFRACTION16chain 'B' and (resid 4 through 45 )B4 - 45
17X-RAY DIFFRACTION17chain 'B' and (resid 46 through 118 )B46 - 118
18X-RAY DIFFRACTION18chain 'B' and (resid 119 through 170 )B119 - 170
19X-RAY DIFFRACTION19chain 'B' and (resid 171 through 254 )B171 - 254

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